Project Summary Renal cell carcinoma (RCC) is a lethal disease whose incidence is on the rise. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. Current targeted molecular strategies, including tyrosine kinase inhibitors (TKIs), have resulted in a doubling of progression-free survival and significant gains in overall survival in ccRCC patients. Despite the therapeutic progress, complete and durable responses have been noted in only a few cases. Moreover, about one quarter of the ccRCC patients are primarily refractory to treatment with TKIs. Our published studies have made it evident that the aberrant activation of PI3K/Akt pathway promotes resistance to TKIs in genitourinary tumors. Our most recent findings reveal that the addition of LDL cholesterol dramatically increases activation of PI3K/Akt signaling in RCC cells and compromises the antitumor efficacy of TKIs both in vitro and in vivo. Based on these findings, we hypothesize that LDL-mediated activation of PI3K/Akt pathway may contribute to intrinsic TKI resistance in ccRCC patients. To test our hypothesis and validate the role of LDL cholesterol in TKI resistance, we propose the following Specific Aims: (1) To enhance the antitumor efficacy of TKIs by modulating cellular cholesterol trafficking; (2) To validate the role of hyperlipidemia in TKI resistance and optimize the in vivo antitumor activity of sunitinib using LXR agonist GW3965. We anticipate that the proposed studies will gain insights that suggest new therapeutic options for the treatment of renal cancer. Targeting the cholesterol supply may be a potential strategy to treat cholesterol-addicted ccRCC and overcome resistance to TKI-based therapeutic regimens.